Bioavailability and Food Effect of the Original Gelatin Formulation and Two New Formulations of Afuresertib in Normal Healthy Volunteers

NCT01827644 | Completed Phase 1

• 1 other identifier: 117313
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a randomized, open-label, sequential, single dose, 4-period crossover study. This study is being conducted to measure the relative bioavailability of the original gelatin capsule (GC) formulation and two new formulations (hydroxypropyl-methylcellulose \[HPMC\] capsule and enteric coated tablet \[ECT\]) of afuresertib (AFU), in the fed and fasted state. The study will be composed of Screening, Treatment, and Follow-up Periods. Screening assessments to determine subject eligibility will be performed within 3 weeks prior to the first dose of study drug in the Treatment Period. Eligible subjects will be randomized to receive 4 of the 6 possible study treatments (A: AFU GC administered in a fasted state, B: AFU GC administered in a fed state, C: AFU HPMC capsule administered in a fasted state, D: AFU HPMC capsule administered in a fed state, E: AFU ECT administered in a fasted state, F: AFU ECT administered in a fed state) in 4 treatment periods (one per treatment period). Subjects will receive a single dose of one of the six study treatments (A, B, C, D, E, F) on Day 1 of each Dosing Period, according to one of the 6 treatment sequences (CEDA, EFAB, ABFC, BDCE, FCBD, DAEF). There will be a minimum of 10 Day washout period between the doses administered in each Treatment Period. A Follow-up visit will be conducted within 10-14 days after the last dose. A subject's total time involved in the study will be approximately 9 weeks. At least 36 subjects will be enrolled in the study, to ensure that at least 6 subjects will be randomized to receive each treatment sequence.

Conditions

Cancer

Keywords

AKT inhibitor; formulation; food effect; bioavailability; GSK2110183

Outcome Measures

Primary Outcomes (1)

• Composite of plasma pharmacokinetics (PK) parameters of afuresertib, following administration with and without food

  Relative bioavailability of afuresertib after single dose of a GC, HPMC capsule and ECT, with and without high fat/calorie meal, will be determined by the following PK parameters: Area under the plasma concentration time curve- from time zero (pre-dose) to infinite time \[AUC(0-inf)\] and from time zero (pre-dose) to last time of quantifiable concentration \[AUC(0-t)\], maximum observed plasma concentration (Cmax), time to Cmax (tmax), observed plasma concentration at 24 hours (C24), and minimal observed plasma concentration (Ct)

  PK samples will be collected at Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose in each dosing period

Secondary Outcomes (6)

• Safety and tolerability of afuresertib as assessed by number of subjects with adverse events (AEs)

  Up to 9 weeks

• Safety and tolerability of afuresertib as assessed by clinical laboratory tests

  Up to 9 weeks

• Safety and tolerability of afuresertib as assessed by concomitant medications review

  Up to 9 weeks

• Safety and tolerability of afuresertib as assessed by electrocardiograms (ECG) measurements

  Up to 9 weeks

• Safety and tolerability of afuresertib as assessed by vital signs measurement

  Up to 9 weeks

Study Arms (6)

Sequence 1

EXPERIMENTAL

Subjects will receive single doses of AFU HPMC capsule administered in a fasted state, AFU ECT administered in a fasted state, AFU HPMC capsule administered in a fed state and AFU GC administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period

Drug: Afuresertib GC - Fasted State; Drug: Afuresertib HPMC capsule - Fasted State; Drug: Afuresertib ECT - Fasted State; Drug: Afuresertib HPMC capsule - Fed State

Sequence 2

EXPERIMENTAL

Subjects will receive single doses of AFU ECT administered in a fasted state, AFU ECT administered in a fed state, AFU GC administered in a fasted state and AFU GC administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period.

Drug: Afuresertib GC - Fasted State; Drug: Afuresertib ECT - Fasted State; Drug: Afuresertib GC - Fed State; Drug: Afuresertib ECT - Fed State

Sequence 3

EXPERIMENTAL

Subjects will receive single doses of AFU GC administered in a fasted state, AFU GC administered in a fed state, AFU ECT administered in a fed state and AFU HPMC capsule administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period.

Drug: Afuresertib GC - Fasted State; Drug: Afuresertib HPMC capsule - Fasted State; Drug: Afuresertib GC - Fed State; Drug: Afuresertib ECT - Fed State

Sequence 4

EXPERIMENTAL

Subjects will receive single doses of AFU GC administered in a fed state, AFU HPMC capsule administered in a fed state, AFU HPMC capsule administered in a fasted state and AFU ECT administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period

Drug: Afuresertib HPMC capsule - Fasted State; Drug: Afuresertib ECT - Fasted State; Drug: Afuresertib GC - Fed State; Drug: Afuresertib HPMC capsule - Fed State

Sequence 5

EXPERIMENTAL

Subjects will receive single doses of AFU ECT administered in a fed state, AFU HPMC capsule administered in a fasted state, AFU GC administered in a fed state and AFU HPMC capsule administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period

Drug: Afuresertib HPMC capsule - Fasted State; Drug: Afuresertib GC - Fed State; Drug: Afuresertib HPMC capsule - Fed State; Drug: Afuresertib ECT - Fed State

Sequence 6

EXPERIMENTAL

Subjects will receive single doses of AFU HPMC capsule administered in a fed state, AFU GC administered in a fasted state, AFU ECT administered in a fasted state and AFU ECT administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period

Drug: Afuresertib GC - Fasted State; Drug: Afuresertib ECT - Fasted State; Drug: Afuresertib HPMC capsule - Fed State; Drug: Afuresertib ECT - Fed State

Interventions

Afuresertib GC - Fasted State DRUG

White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state

Sequence 1; Sequence 2; Sequence 3; Sequence 6

Afuresertib HPMC capsule - Fasted State DRUG

White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state

Sequence 1; Sequence 3; Sequence 4; Sequence 5

Afuresertib ECT - Fasted State DRUG

White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state

Sequence 1; Sequence 2; Sequence 4; Sequence 6

Afuresertib GC - Fed State DRUG

White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state

Sequence 2; Sequence 3; Sequence 4; Sequence 5

Afuresertib HPMC capsule - Fed State DRUG

White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state

Sequence 1; Sequence 4; Sequence 5; Sequence 6

Afuresertib ECT - Fed State DRUG

White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state

Sequence 2; Sequence 3; Sequence 5; Sequence 6

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Male or female between 18 and 40 years of age inclusive, at the time of signing the informed consent
• Body weight \>=50 kilograms (kg) and body mass index (BMI) \<=32 kg/m\^2 (square meter)
• A female subject is eligible to participate if she is of: (A) Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea (B) Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at Screening and prior to dosing, AND: agrees to use one of the acceptable contraception methods
• Male subjects with female partners of child-bearing potential must agree to use one of the acceptable contraception methods.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5 x Upper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Based on single or averaged corrected QT interval (QTc) values of triplicate electrocardiograms (ECGs) obtained over a brief recording period: QTc \<450 milliseconds (msec) or QTc \<480 msec in subjects with Bundle Branch Block

You may not qualify if:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of gastroesophageal reflux disease (GERD), dyspepsia, gastrointestinal (GI) bleeding, GI surgery that could affect motility
• History of atrial arrhythmias
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to heparin or heparin-induced thrombocytopenia
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation
• Use of prescription or non-prescription medications, vitamins, and dietary or herbal supplements (including St John's Wort) within 7 days (or 14 days if the drug/supplement is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study drug until completion of the Follow-up Period, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study
• Unable to abstain from smoking tobacco or the use of nicotine-containing products while admitted to the clinic
• Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of Study Drug on Day 1 of Dosing Period 1, until completion of the Follow-up Period
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening
• History of heavy use of tobacco- or nicotine-containing products within 6 months prior to Screening.
• A positive drug/alcohol screen at Screening or upon check-in to the clinic on Day -1 of each Dosing Period
• A positive test for Human Immunodeficiency Virus (HIV) antibody
• Pregnant females as determined by positive serum hCG test at Screening or prior to dosing.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Melbourne, Victoria, 3004, Australia

Location

Related Links

• Results for study 117313 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2013
• First Posted: April 9, 2013
• Study Start: April 24, 2013
• Primary Completion: July 12, 2013
• Study Completion: July 12, 2013
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

AU (1)